Compounds with affinity for estrogen receptors have found long-standing utility in the treatment of a variety of medical indications. Despite the long history of the field there still is a need for more effective, safer and more economical compounds than the existing ones. For the control or prevention of estrogen sensitive tumor growth, compounds are needed which are antagonists or partial antagonists.
The discovery of subtypes of estrogen receptors, there being an α-subtype (ERα) and a β-subtype (ERβ) of such receptors (Mosselman et al., FEBS Letters vol. 392 (1996) pp. 49-53 as well as EP-A-0 798 378), offers the possibility to influence one particular subtype of those two receptors more selectively, immanently resulting in more effective treatments or treatments with less side effects. Since these receptors have a different distribution in human tissue, the finding of compounds which possess a selective affinity for either of the two is an important technical progress, making it possible to provide a more selective treatment in estrogen-receptor related medical treatments with a lower burden of estrogen-related side-effects.
Attempts to replace the steroid skeleton with other cyclic structures have led to explorations of a tetrahydrobenzfluorene skeleton (Tedesco et al.; Bioorganic Med Chem Letters Vol 11, pp 1281-1284; 2001) as compounds with influence on estrogen receptors. Compounds with a differing tetrahydrobenzfluorene skeleton were found, which within strict stereochemical requirements, display very selective actions on estrogen receptors.
It is found that compounds having the formula I
wherein    the O—(CH2)n—N(R1,R2) substituent on the phenyl ring can be in meta or para position;    n is 2-4    Re and ′Re are OH, optionally independently etherified or esterified;    R1 and R2 are independently (1C-4C)alkyl, (2C-4C)alkenyl, hydroxy(2C-4C)alkyl, (1C-3C)alkoxy(2C-4C)alkyl, aryl or aryl(1C-2C)alkyl; or R1 and R2 together with the nitrogen form an aromatic or non-aromatic heterocyclic ring structure, optionally mono- or poly-substituted with (1C-4C)alkyl, (2C-4C)alkenyl, hydroxy(1C-2C)alkyl, (1C-2C)alkoxy(1 C-3C)alkyl or aryl.
The compounds of the invention can be used in medical treatments aimed to selectively influence estrogen receptors (ERα, and ERβ) in an organism, being a human or an animal.